Twin studies have provided decisive evidence for the hereditary nature of body weight regulation,1-3 demonstrating that individual differences in tendencies toward weight gain could be explained by an interaction between genotype and the nutritional environment.4 The exact mechanisms that connect genes to susceptibility to weight gain in common obesity remain unknown. The goal of this work is to identify central nervous system (CNS) mechanisms that contribute to genetic susceptibility to weight gain in the modern food environment. To accomplish this goal, we will use neuroimaging to assess potential CNS mechanisms and use twin research methods to establish the mechanism[unreadable]s genetic basis and link it to susceptibility to obesity. We, and others,5-9 have used functional magnetic resonance imaging (fMRI) to demonstrate that visual images of food powerfully stimulate brain areas active in regulating energy homeostasis, reward, and cognitive control of behavior.10 Whether or not these neural responses have a genetic basis is unknown. Further, our preliminary data suggest an effect of food ingestion on the brain response to visual food cues, the strength of which may provide a robust, neurobiological measure of satiety in humans. This proposal addresses these issues. We also apply fMRI to investigate obesity pathogenesis, focusing on theories that altered CNS reward processing or impaired satiety responses drive food intake in excess of nutritional needs. By using genetically informative twin samples, we will provide new data on the extent that observed differences in brain response to food cues among obese persons8, 11 represent genetic predispositions vs. environmentally-mediated or acquired traits. We will implement our established fMRI protocol10 for measuring brain response to visual food cues in 2 twin samples recruited from the University of Washington Twin Registry. A random sample of 20 monozygotic pairs will allow us to: 1) test whether inherited factors can account for individual differences in brain response to visual food cues and 2) determine if the change in brain response with food intake is a marker of satiety. We will also assemble a targeted sample of 21 monozygotic and 21 same-sex dizygotic twin pairs discordant for body mass index to: 1) determine whether body fat mass is associated with brain response to visual food cues, and establish whether this association is mediated by inherited or acquired factors and 2) determine if the change in brain response to food cues is associated with body fat mass. All twins will be genotyped for a variant allele in the fat mass and obesity-associated (FTO) gene, one of the most common and most reproducible of identified obesity susceptibility genes, to compare brain response to visual food cues in twins with and without the FTO gene variant. These studies will advance scientific knowledge regarding obesity pathogenesis and inform prevention and intervention efforts.